HLA-C and -Bw typing of couples with unexplained recurrent miscarriages

doi:10.1016/S0165-0378(97)00073-9

Journal of Reproductive Immunology

Volume 37, Issue 1, 15 December 1997, Pages 63-77

https://doi.org/10.1016/S0165-0378(97)00073-9 Get rights and content

Abstract

There is now evidence that the classical HLA class I molecule HLA-C is expressed on extravillous trophoblasts together with non-classical HLA-G molecules. Since clones of NK-cells are inhibited differently by supertypic epitopes associated with HLA-C and -B alleles we found it of interest to study HLA-C and -Bw polymorphism in 35 couples with recurrent miscarriage and 30 control couples with normal fecundity. All HLA assignments were undertaken by DNA techniques. The distribution of HLA-C alleles or the HLA-C associated supertypic epitopes recognized by NK1 or NK2 clones was not significantly different between patients and controls. The distribution of couples according to the number of NK1 and NK2 epitopes in the couple was similar in patients and controls. With respect to the HLA-Bw epitopes recognized by NKB1 clones, in 46% of the couples with recurrent miscarriage none of the spouses carried the HLA-Bw4 epitope compared with only 17% of the control couples (P<0.02). It is concluded that the HLA-Bw4 epitope is carried more frequently by couples with normal fecundity than couples with recurrent miscarriage. The fetuses of couples with recurrent miscarriage are thus expected to lack expression of HLA-Bw4 epitopes on the trophoblast more often than fetuses of normal couples which might be of importance for the inhibition of NK-cell mediated antitrophoblast cytotoxicity.

References (39)

M. Bennett
Hybrid resistance:‘negative’ and ‘positive’ signalling of murine natural killer cells
G. Eroglu et al.
Impact of histocompatibility antigens on pregnancy outcome
Am. J. Obstet. Gynecol.
(1992)
C.A. Sunderland et al.
The expression of major histo-compatibility antigens by human chorionic villi
J. Reprod. Immunol.
(1981)
K.L. Arnett et al.
HLA Class I nucleotide sequences, 1995
Tissue Antigens
(1995)
R. Biassoni et al.
Amino acid substitutions can influence the natural killer (NK-)-mediated recognition of HLA-C molecules. Role of Serine-77 and Lysine-80 in the target cell protection from lysis mediated by ‘group 2’ or ‘group 1’ NK clones
J. Exp. Med.
(1995)
J.G. Bodmer et al.
Nomenclature for factors of the HLA system, 1995
Tissue Antigens
(1995)
J. Boucraut et al.
HLA-E is the only class I gene that escapes CpG methylation and is transcriptionally active in the trophoblast-derived human cell line JAR
Immunogenetics
(1993)
M. Bunce et al.
Improvements in HLA-C typing using sequence-specific primers (PCR-SSP) including the definition of HLA-Cw9 and Cw10 and a new allele HLA-Cw7/8v′
Tissue Antigens
(1994)
M. Bunce et al.
Rapid DNA typing for HLA-C using sequence-specific primers (PCR-SSP): identificaton of serological and non-serological defined HLA-C alleles including several new alleles
Tissue Antigens
(1994)
M. Cella et al.
NK3-specific natural killer cells are selectively inhibited by Bw4-positive HLA alleles with isoleucine 80
J. Exp. Med.
(1994)

O.B. Christiansen et al.

Prognostic significance of maternal DR histocompatibility types in Danish women with recurrent miscarriages

Hum. Reprod.

(1993)

O.B. Christiansen et al.

HLA Class II alleles confer susceptibility to recurrent fetal losses in Danish women

Tissue Antigens

(1994)

M. Colonna et al.

HLA-C is the inhibitory ligand that determines dominant resistance to lysis by NK1- and NK2-specific natural killer cells

M. Colonna

Specificity and function of immunoglobulin superfamily NK cell inhibitory and stimulatory receptors

Immunol. Rev.

(1997)

C.B. Coulam et al.

Association between major histocompatibility antigen and reproductive performance

Am. J. Reprod. Immunol. Microbiol.

(1987)

G. Cudkowicz et al.

Peculiar immunobiology of bone marrow allografts

J. Exp. Med.

(1971)

A. D'Andrea et al.

Molecular cloning of NKB1: a natural killer cell receptor for HLA-B allotypes

J. Immunol.

(1995)

A. Grabowska et al.

Human trophoblast cells in culture express an unusual major histocompatibility complex class I-like antigen

Am. J. Reprod. Immunol.

(1990)

N. Grunnet et al.

Increased frequency of HLA-DRw14b(w6)-associated RFLP in Greenlanders of Eskimo origin

Tissue Antigens

(1991)

Cited by (16)

HLA associations and HLA sharing in recurrent miscarriage: A systematic review and meta-analysis
2015, Human Immunology
Citation Excerpt :
All studies, which investigate HLA sharing and used molecular typing method, mentioned whether they used high or low resolution typing. Three studies used high resolution [59–61] and five used low resolution [45,53,62–64]. A greater risk for bias was that only 14 out of 21 studies which investigated HLA sharing defined adequately which antigens and alleles were used to calculate sharing.
The aim of this meta-analysis was to evaluate whether specific maternal HLA alleles and HLA sharing of couples are associated with the occurrence of recurrent miscarriage (RM).
A systematic literature search was performed for studies that evaluated the association between HLA alleles, HLA sharing and RM. RM was defined as three or more consecutive unexplained miscarriages and a control group was included of women with at least one live birth and no miscarriages in their history. Meta-analyses were performed and the pooled odds ratio (OR) was calculated.
We included 41 studies. Selection bias was present in 40 studies and information bias in all studies. Meta-analyses showed an increased risk of RM in mothers carrying a HLA-DRB1*4 (OR 1.41, 95% CI 1.05–1.90), HLA-DRB1*15 (OR 1.57, 95% CI 1.15–2.14), or a HLA-E*01:01 allele (OR 1.47, 95% CI 0.20–1.81), and a decreased risk with HLA-DRB1*13 (OR 0.63, 95% CI 0.45–0.89) or HLA-DRB1*14 (OR 0.54, 95% CI 0.31–0.94). Pooling results for HLA sharing showed that HLA-B sharing (OR 1.39, 95% CI 1.11–1.75) and HLA-DR sharing (OR 1.57, 95% CI 1.10–1.25) were both associated with the occurrence of RM.
Although the present systematic review and meta-analysis demonstrates that specific HLA alleles and HLA sharing are associated with RM, a high degree of bias was present and therefore observed results should be interpreted carefully.
HLA-C C1C2 heterozygosity may protect women bearing the killer immunoglobulin-like receptor AA genotype from spontaneous abortion
2011, Journal of Reproductive Immunology
Citation Excerpt :
KIR ligand (HLA class I) sharing between the mother and her partner or fetus has been extensively studied. Paradoxically, although HLA-C is the only polymorphic HLA molecule expressed on extravillous trophoblasts, reports on the effect of HLA-C allele sharing on RSA risk are scarce and contradictory (Christiansen et al., 1997; Beydoun and Saftlas, 2005). We observed almost five times lower frequencies of C1C2 women pregnant by C2C2 males in the miscarriage than in the control group, suggesting a protection from abortion with this combination.
Spontaneous abortion is the most common complication of human pregnancy. Natural killer (NK) cells expressing killer immunoglobulin-like receptors (KIRs), which may recognize HLA-C (i.e. its C1 or C2 groups) on trophoblast cells, constitute a large leukocyte population in the endometrium. This study investigated whether genetic polymorphisms in the KIR and HLA-C genes are risk factors for spontaneous abortion. One hundred and twenty-five couples with at least two spontaneous abortions, including eighty-five couples with idiopathic recurrent abortion (RSA; three or more abortions), and 117 control couples (with two or more healthy-born children) were tested. The frequencies of the individual KIR genes in the patients were similar to those in the controls. In the group of KIR AA women with HLA-C C2C2 partners, the HLA-C C1C2 heterozygotes were present in the controls but not in the patients (p = 0.015 for all patients and p = 0.0048 for RSA, but both comparisons lost significance after Bonferroni correction), whereas both homozygotes, C1C1 and C2C2, were absent in the control women but present among the aborting ones. Therefore, our results suggest that among KIR AA women who have HLA-C C2C2 partners, HLA-C heterozygous females show a trend towards an increased chance of successful pregnancy.
Evidence-based investigations and treatments of recurrent pregnancy loss
2005, Fertility and Sterility
Citation Excerpt :
Although the exact functions of these molecules in the placenta have not been fully elucidated, they seem to participate in an intrinsic network that guarantees the survival of the fetal allograft. However, studies on polymorphisms of HLA-C and -E or sharing of HLA-C or -E alleles in patients with RPL could not provide evidence for a key role of those antigens in the pathogenesis of RPL (102–106). Human leukocyte antigen G is the dominant HLA antigen at the maternal–fetal interface, and different HLA-G alleles, including a functional null-allele, G*0105N, has been identified (107).
To give an overview of currently used investigations and treatments offered to women with recurrent pregnancy loss (RPL) and, from an evidence-based point of view, to evaluate the usefulness of these interventions.
Ten experts on epidemiologic, genetic, anatomic, endocrinologic, thrombophilic, immunologic, and immunogenetic aspects of RPL discussed methodologic problems threatening the validity of research in RPL during and after an international workshop on the evidence-based management of RPL.
Most RPL patients have several risk factors for miscarriage, and an extensive investigation for all major factors should always be undertaken. There is an urgent need for agreement concerning the thresholds for detecting what is normal and abnormal, irrespective of whether laboratory tests or uterine abnormalities are concerned. A series of lifestyle factors should be reported in future studies of RPL because they might modify the effect of laboratory or anatomic risk factors. More and larger randomized controlled trials, including trials of surgical procedures, are urgently needed, and to achieve this objective multiple centers have to collaborate. Current meta-analyses evaluating the efficacy of treatments of RPL are generally pooling very heterogeneous patient populations and treatments. It is recommended that future meta-analyses look at subsets of patients and treatment protocols that are more combinable.
Maternal natural killer cell immunoglobulin receptor genes and human leukocyte antigen-C ligands influence recurrent spontaneous abortion in the han Chinese population
2018, Experimental and Therapeutic Medicine
Immunologic abnormalities, treatments, and recurrent pregnancy loss: What is real and what is not?
2016, Clinical Obstetrics and Gynecology
Recurrent Pregnancy Loss in Women with Killer Cell Immunoglobulin-Like Receptor KIR2DS1 is Associated with an Increased HLA-C2 Allelic Frequency
2016, American Journal of Reproductive Immunology

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Clinical studyHLA-C and -Bw typing of couples with unexplained recurrent miscarriages

Abstract

Am. J. Obstet. Gynecol.

J. Reprod. Immunol.

HLA Class I nucleotide sequences, 1995

Tissue Antigens

Amino acid substitutions can influence the natural killer (NK-)-mediated recognition of HLA-C molecules. Role of Serine-77 and Lysine-80 in the target cell protection from lysis mediated by ‘group 2’ or ‘group 1’ NK clones

J. Exp. Med.

Nomenclature for factors of the HLA system, 1995

Tissue Antigens

HLA-E is the only class I gene that escapes CpG methylation and is transcriptionally active in the trophoblast-derived human cell line JAR

Immunogenetics

Improvements in HLA-C typing using sequence-specific primers (PCR-SSP) including the definition of HLA-Cw9 and Cw10 and a new allele HLA-Cw7/8v′

Tissue Antigens

Rapid DNA typing for HLA-C using sequence-specific primers (PCR-SSP): identificaton of serological and non-serological defined HLA-C alleles including several new alleles

Tissue Antigens

NK3-specific natural killer cells are selectively inhibited by Bw4-positive HLA alleles with isoleucine 80

J. Exp. Med.

Prognostic significance of maternal DR histocompatibility types in Danish women with recurrent miscarriages

Hum. Reprod.

HLA Class II alleles confer susceptibility to recurrent fetal losses in Danish women

Tissue Antigens

HLA-C is the inhibitory ligand that determines dominant resistance to lysis by NK1- and NK2-specific natural killer cells

Specificity and function of immunoglobulin superfamily NK cell inhibitory and stimulatory receptors

Immunol. Rev.

Association between major histocompatibility antigen and reproductive performance

Am. J. Reprod. Immunol. Microbiol.

Peculiar immunobiology of bone marrow allografts

J. Exp. Med.

Molecular cloning of NKB1: a natural killer cell receptor for HLA-B allotypes

J. Immunol.

Human trophoblast cells in culture express an unusual major histocompatibility complex class I-like antigen

Am. J. Reprod. Immunol.

Increased frequency of HLA-DRw14b(w6)-associated RFLP in Greenlanders of Eskimo origin

Tissue Antigens

Clinical study
HLA-C and -Bw typing of couples with unexplained recurrent miscarriages